1. FIELD OF THE INVENTION
The present invention is directed to a method for preparing certain selected pro-theophylline derivatives. More particularly, the present invention is directed to a method for preparing certain "pro-drug" forms of theophylline useful in the treatment of asthma in warm-blooded animals, e.g., humans.
The compounds prepared by the method of this invention are described in pending patent application, Ser. No. 463,092, filed Apr. 22, 1974, and entitled "USEFUL PRO-DRUG FORMS OF THEOPHYLLINE," the subject matter of which is incorporated herein by reference.
2. DESCRIPTION OF THE PRIOR ART
Theophylline, normally administered as the ethylenediamine salt (Aminophylline) or choline salt, is a useful and potent bronchodilator commonly prescribed for the treatment of bronchial asthma. Because it is readily soluble, Aminophylline has for many years been accepted as an effective bronchodilator when given orally. However, Aminophylline in solution becomes highly alkaline and is hydrolized by the gastric juice with resultant gastric irritation from the free theophylline liberated.
5 to 12 mcg./ml of whole blood or 10 to 25 mcg./ml of plasma are the relative blood levels of theophylline generally accepted as necessary to achieve effective bronchodilation. See, E. G. Truitt, V. A. McKusick, J. C. Krantz, Jr., Pharm. Exp. Ther., 100, 309 (1950) and M. Warwick Turner, Brit. Med. Jr., 2, 67 (1957), respectively. These theophylline blood levels are, however, difficult to attain, since as a result of the gastrointestinal upset experienced, patients cannot tolerate an adequate therapeutic dose of the drug. Reports in the literature with a variety of theophylline derivatives have often shown not only that theophylline blood levels achieved are below the values required for the relief of a bronchospasm, but also that even when these therapeutic levels are obtained, they fall off extremely rapidly in the first few hours following administration of the drug. Thus, repeated dosing of the patient about every 3 to 4 hours is necessary. See, E. G. Truitt, V. A. McKusick, J. C. Krantz, Jr., and M. Turner-Warwick, and R. H. Jackson, J. I. McHenry, S. B. Moreland, W. J. Raymer, and R. L. Etter, Dis. Chest., 45, 75 (1964), and J. Schluger, J. T. McGuinn, and D. J. Hennesey, Amer. J. Med. Sci. 233, 296 (1957), respectively.
In addition, even when therapeutic blood levels of theophylline are achieved, the amount of theophylline administered to a patient is so excessive that the therapeutic blood level achieved approaches and often reaches toxicity.
In one attempt to overcome the above disadvantages associated with administering theophylline, certain individuals have prepared a continuous-release formulation, such that the release rate of theophylline is dependent upon the formulation medium into which it is incorporated. That is, sustained therapeutic blood levels of theophylline are achieved through the use of a particular pharmaceutical formulation rather than chemical modification of the theophylline molecule. See, C. Boroda, R. B. Miller, S. T. Leslie, E. G. Nicol and I. Thompson, Clin. Pharm., 383 (1973) and D. McIntosh, Brit. J. Clin. Pharm., 12, 233 (1971) respectively.
Some theophylline derivatives, analogous to the compounds of formula (I) described hereinabove, have been prepared and described in the literature for the purpose of studying their chemistry per se, without any indication of any pharmaceutical utility. For instance, 7-acetyltheophylline was reported in three different articles. See, for instance, T. Higuchi, H. K. Lee and Ian H. Pittman; Farm. Aikak. 80, 55 (1971) and Y. Ishido, A. Hosono, S. Isome, A. Maruyama, and T. Sato, Bull. Chem. Soc. Japan, 37, 1389 (1964), respectively.
7-acetyltheophylline and 7-benzoyltheophylline were reported in H. Biltz, and K. Struffe, Ann., 404, 170 (1914) as well.
7-propionyltheophylline and 7-butyryltheophylline have also been reported in the literature. See, Y. Ishido, A. Hosono, S. Isome, A. Maruyama, and T. Sato, supra.
Finally, United States Pat. No. 2,729,643 discloses certain 7-carboxamidotheophylline derivatives useful as diuretics.
As for the compounds of formula (II) described herein above, no prior art of structural chemical or pharmacological significance is known.
United States Patent Application, Ser. No. 463,092 ('092), referred to earlier, describes a basic synthesis scheme for preparing the compounds encompassed by formulas (I) and (II) of this Application. See, page 7, line 2 through page 8, line 33 of the '092 application, inclusive.
Admittedly, while all the compounds encompassed within formulas (I) and (II) of this invention can be prepared by the synthesis scheme described in the '092 application, such compounds are deficient from the standpoint of (1) substantial purity, and, moreover, (2) substantial stability. Furthermore, the synthesis scheme disclosed in the '092 application is quite expensive, especially from the standpoint of commercial acceptance and exploitation.
Therefore, it is readily apparent that a need exists for a means to inexpensively prepare the compounds of formula (I) and (II) in a more (1) pure and (2) stable form.